Abstract

Introduction

To alleviate human immunodeficiency virus (HIV)-related symptoms (e.g., pain, nausea, loss of appetite) people living with HIV (PLWH) often report using cannabis (CB). Of the 38 million PLWH, nearly half demonstrate neurocognitive impairments highlighting a need to clarify the brain-based manifestations of such impairments. Emerging evidence suggests that HIV infection and chronic CB use are both separately linked with alterations in default mode network (DMN) functional connectivity. Prior studies have also demonstrated that resting-state connectivity networks correlate with underlying structural connections between functional nodes. Elucidating the relationship between CB use, HIV infection, and DMN structural connectivity is important for improved understanding of the impact of these conditions on neurocognitive functions, and to better inform patients, healthcare providers, and policy makers about medicinal and/or recreational CB use among PLWH.

Methods

Using diffusion weighted imaging (DWI) data, we characterized the structural connectivity profiles of DMN regions among 100 participants stratified into four groups based on HIV serostatus and CB use history (HIV+/CB+, n=27; HIV+/CB-, n=24; HIV-/CB+, n=27; HIV-/CB-, n=22). To establish the structural connectivity profiles across DMN nodes a deterministic fiber tractography algorithm (FA threshold = 0.20, angle threshold = 30°, min length = 30 mm, max length = 500mm, seed count = 100,000) was used to track bilateral cingulum tracts (CT), the bilateral superior fronto-occipital fasciculus (FOF), and the genu of the corpus callosum (CC). Participants completed a battery of well-validated tasks to quantify behavioral measures of inhibitory control, error processing, and general cognitive control. To explore the influence of HIV and CB on structural connectivity, first a 2x2 ANOVA, including age and sex as covariates was conducted on individual white matter tract DVs. Then, for the tracts showing group-level differences, a mixed linear regression was conducted with an emphasis on the HIVxCB interaction when considering DTI metrics and behavioral measures.

Results

The ANOVA analysis of white matter tracts identified significant group differences in tract number for the right CT between HIV groups (Fig. 1A), tract volume of the left CT between CB groups (Fig. 1B), and the FA values of the right superior FOF between CB groups (Fig. 1C). Tukey post-hoc tests revealed that HIV+ (vs. HIV-) groups had more right cingulum tracts, and CB+ (vs. CB-) groups had greater tract volume in the left cingulum and higher FA in the right superior FOF. The linear regression analyses on the left CT, right superior FOF, and right CT identified a significant interaction between CB and FA in the left cingulum, such that CB+ groups demonstrated more preservative errors than the CB- groups (Fig. 2A). Across all participants, left cingulum tract volume was positively associated with general processing speed (Fig. 2B).

Conclusions

The left cingulum tract connects the posterior cingulate cortex, (para)hippocampal regions, entorhinal cortex, and the medial temporal lobes, which are areas commonly linked with both memory and emotional regulation. Our results suggest that the left cingulum tract may be more susceptible to CB-related structural connectivity alterations regardless of HIV serostatus. These results also suggest that DMN structural connectivity alterations may contribute to more preservative errors reflecting reduced cognitive flexibility (shifting). Taken together, these outcomes provide enhanced insight into the neurobiological underpinnings of HIV and CB-related impacts on cognition.